Malignant or benign tumors whose cell growth is controlled by sexual hormones include prostatic tumors, benign prostatic hyperplasia and breast carcinomas. Benign prostatic hyperplasia can be caused by a reduction of androgens, which is associated with a relative increase in the share of estrogens in the hormone balance.
However, not only the reduction of androgens but also increased estrogen production caused by increased aromatase activity in males is regarded today as a cause of benign prostatic hyperplasia. The rich connective tissue of the prostate is particularly responsive to estrogens with activated growth. Benign prostatic hyperplasia is caused and continues to grow due to faulty control of hormones. Thus an "organ" grows but not a type of tissue, i.e. benign prostatic hyperplasia consists of connective tissue and glandular epithelium, which form irregular nodes, e.g. glands without the associated excretory duct. Now both types of cells require two different and opposite hormones for their growth impulse. The glandular cells respond to androgens (e.g. testosterone), the connective tissue, on the other hand, reacts to estrogens (e.g. estradiol).
Symptoms which arise in prostatic hyperplasia include an increased desire to urinate, problems when passing water, later residual urine, and lastly, an acute urine blockage, because due to the expanding tissue in the surroundings of the urethra, the passing of water is choked and is displaced. It is therefore necessary for therapy, which is to improve the miction of a patient made more difficult by the tumor, to increase the miction volume and thereby to reduce or overcome the residual amount of urine.
The enzyme aromatase plays an important part in the normal biosynthesis of the female sexual hormone, estradiol. This enzyme catalyzes the conversion of androgens into estrogens, e.g. of the initially arising testosterone into estradiol (aromatization). Thus the daily use of testosterone in the case of females because of this physiological synthesis route amounts to about 0.1 mg.
Aromatase is an enzyme system of cytochrome P-450 with a NADPH-dependent cytochrome reductase. Non-steroidal aromatase inhibitors (e.g. imidazoles, aminoglutethimide) take effect primarily as inhibitors by reversible complex formation with a haemo group of the enzyme, whereas steroidal inhibitors bind firmly and stop the enzyme system for long periods.
In females, as well as, on a lower level, in males, the conversion of androgens into estrogens is inhibited by aromatase inhibitors, so that a reduction of the estrogen level results. Such aromatase inhibitors were previously used for the treatment of breast carcinoma and in the first tests for cases of benign prostatic hyperplasia. Because they are still disproportionately expensive and in contrast to the carcinoma, the benign prostatic hyperplasia has a comparatively low degree of suffering, they are not represented on the market for prostatic preparations.
Because the agents and substances previously used in the treatment of prostatic carcinoma are produced in very expensive synthetic processes, there is a need for effective substances for aromatase inhibition, which can be used successfully for the treatment of breast carcinoma and prostatic hyperplasia, but which either occur naturally or are synthesized relatively economically.
Oxooctadecadienic acids are known compounds and are used in medicine for specific purposes. For example, in Japanese laid open application JP 62-164620-Al, the use of the unsaturated fatty acid in hydroxy form, is named as an anti-hypertensive agent, and an anti-arteriosclerosis effect is ascribed very generally to unsaturated fatty acids. In a further publication, EP-A-O-097 059, topical compositions which contain these hydroxy acids are suggested for skin treatment.
From Chemical Abstracts, Vol. 93 (1980), NO. 202348a, it is known that 9-hydroxy-10, 12-octadecadienic acid is an (in-vitro) metabolic product of linoleum acid in VX.sub.2 -tumor tissue culture. In this connection the metabolism of this fatty acid is discussed with respect to its part in the calcium level of bones.
From Chemical Abstracts, Vol. 85 (1976), No. 173098w, 8-hydroxy-10(trans)-12(Cis)-octadecadienic acid and 13-hydroxy-9(cis)-11(trans)-octadecadienic acid as well as the acids oxidized to keto form of these two named acids as well as partial their methylesters are known. These acids can be isolated from the mitochondria of bovine hearts.
From Chemical Abstracts, Vol. 106 (1987), No. 38127k, lastly, 9-hydroxy-10(trans)-12(cis)-octadecadienic acid is known which is used as a protective substance in rice plants. In the two last-named publications, however, no indication is given of the pharmacological properties of the acids described there. In particular, nothing is known about a pharmacological activity of the oxoctadecadienic acids.